Fangchinoline induces antiviral response by suppressing STING degradation.

The stimulator of interferon genes (STING), an integral adaptor protein in the DNA-sensing pathway, plays a pivotal role in the innate immune response against infections. Additionally, it presents a valuable therapeutic target for infectious diseases and cancer. We observed that fangchinoline (Fan), a bis-benzylisoquinoline alkaloid (BBA), effectively impedes the replication of vesicular stomatitis virus (VSV), encephalomyocarditis virus (EMCV), influenza A virus (H1N1), and herpes simplex virus-1 (HSV-1) in vitro. Fan treatment significantly reduced the viral load, attenuated tissue inflammation, and improved survival in a viral sepsis mouse model. Mechanistically, Fan activates the antiviral response in a STING-dependent manner, leading to increased expression of interferon (IFN) and interferon-stimulated genes (ISGs) for potent antiviral effects in vivo and in vitro. Notably, Fan interacts with STING, preventing its degradation and thereby extending the activation of IFN-based antiviral responses. Collectively, our findings highlight the potential of Fan, which elicits antiviral immunity by suppressing STING degradation, as a promising candidate for antiviral therapy.

Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody-Drug Conjugate for Treatment of CLDN18.2-Positive Cancers.

Gastric and pancreatic cancers are malignancies of high unmet clinical need. Expression of CLDN18.2 in these cancers, coupled with it's absence from most normal tissues, provides a potential therapeutic window against this target. We present preclinical development and characterization of a novel therapeutic mAb and antibody-drug conjugate (ADC) targeting CLDN18.2. A humanized CLDN18.2 specific mAb, CLDN18.2-307-mAb, was generated through immunization in mice followed by full humanization of the mouse mAb sequences. Antibody clones were screened by flow cytometry for selective binding to membrane bound CLDN18.2. A CLDN18.2-directed ADC (CLDN18.2-307-ADC) was also generated by conjugating MMAE to CLDN18.2 mAb using a cleavable linker. Tissue expression of CLDN18.2 was determined by IHC assay using a CLDN18.2-specific mAb. CLDN18.2-307-mAb binds with high affinity to CLDN18.2-positive (CLDN18.2+) cells and induces antibody-dependent cell-mediated cytotoxicity (ADCC). Treatment with this CLDN18.2-mAb blocked the growth of CLDN18.2+ gastric and pancreas cancer cell line xenograft (CDX) models. Upon binding to the extracellular domain of this target, the CLDN18.2-ADC/CLDN18.2 protein was internalized and subsequently localized to the lysosomal compartment inducing complete and sustained tumor regressions in CLDN18.2+ CDXs and patient-derived pancreatic cancer xenografts (PDX). A screen of human cancer tissues, by IHC, found 58% of gastric, 60% of gastroesophageal junction, and 20% of pancreatic adenocarcinomas to be positive for membrane expression of CLDN18.2. These data support clinical development of the CLDN18.2-307-mAb and CLDN18.2-307-ADC for treatment of CLDN18.2+ cancers. Both are now being investigated in phase I clinical studies.

Allogeneic hematopoietic stem cell transplantation corrects ligase IV deficiency.

BACKGROUND: Mutations in the DNA ligase IV (LIG4) gene cause a rare autosomal recessive disorder called LIG4 deficiency syndrome. The LIG4 deficiency is featured by severe disorders, including combined immunodeficiency disease, special face ("bird-head-like" face), developmental delays, pancytopenia, and radiosensitivity. Currently there are no curative treatment options except potentially by performing a hematopoietic stem cell transplantation (HSCT). CASE PRESENTATION: Here we reported the clinical course of a 4 and 1/2-year-old Chinese female with LIG4-deficiency featured with pancytopenia, severe growth retardation (weight of 13.5 kg, < 3rd percentile), length of 100 cm (<2d percentile), head circumference of 46 cm (<3rd percentile), and mild microcephaly. Despite regular IVIG administrations (5 g, once a month), the patient's thrombocytopenia had progressed. Eventually, the patient received HSCT that successfully normalized the LIG4 syndrome associated pancytopenia and corrected the LIG4 mutation. Despite progress the patient succumbed to thrombotic microangiopathy more than 3 months after HSCT. CONCLUSIONS: This case reports an example of partially successful HSCT as a treatment option for LIG4 syndrome. It is possible that individual factors influence the therapeutic effect of HSCT in LIG4 deficiency.

Preclinical Efficacy of the Antibody-Drug Conjugate CLDN6-23-ADC for the Treatment of CLDN6-Positive Solid Tumors.

PURPOSE: Claudin-6 (CLDN6) is expressed at elevated levels in multiple human cancers including ovarian and endometrial malignancies, with little or no detectable expression in normal adult tissue. This expression profile makes CLDN6 an ideal target for development of a potential therapeutic antibody-drug conjugate (ADC). This study describes the generation and preclinical characterization of CLDN6-23-ADC, an ADC consisting of a humanized anti-CLDN6 monoclonal antibody coupled to monomethyl auristatin E (MMAE) via a cleavable linker. EXPERIMENTAL DESIGN: A fully humanized anti-CLDN6 antibody was conjugated to MMAE resulting in the potential therapeutic ADC, CLDN6-23-ADC. The antitumor efficacy of CLDN6-23-ADC was assessed for antitumor efficacy in CLDN6-positive (CLDN6+) and -negative (CLDN6-) xenografts and patient-derived xenograft (PDX) models of human cancers. RESULTS: CLDN6-23-ADC selectively binds to CLDN6, versus other CLDN family members, inhibits the proliferation of CLDN6+ cancer cells in vitro, and is rapidly internalized in CLDN6+ cells. Robust tumor regressions were observed in multiple CLDN6+ xenograft models and tumor inhibition led to markedly enhanced survival of CLDN6+ PDX tumors following treatment with CLDN6-23-ADC. IHC assessment of cancer tissue microarrays demonstrate elevated levels of CLDN6 in 29% of ovarian epithelial carcinomas. Approximately 45% of high-grade serous ovarian carcinomas and 11% of endometrial carcinomas are positive for the target. CONCLUSIONS: We report the development of a novel ADC, CLDN6-23-ADC, that selectively targets CLDN6, a potential onco-fetal-antigen which is highly expressed in ovarian and endometrial cancers. CLDN6-23-ADC exhibits robust tumor regressions in mouse models of human ovarian and endometrial cancers and is currently undergoing phase I study.

Nuanxinkang prevents the development of myocardial infarction-induced chronic heart failure by promoting PINK1/Parkin-mediated mitophagy.

BACKGROUND: Mitochondrial dysfunction is an important pathological feature of chronic heart failure (CHF). Regulation of mitophagy can effectively maintain mitochondrial homeostasis and energy metabolism, thereby inhibiting the development of CHF. Nuanxinkang (NXK), a Chinese herbal compound preparation, has significant cardioprotective effects on CHF; however, its underlying mechanism on mitophagy has not been completely clarified. This research intended to investigate the mechanism of NXK in treating myocardial infarction (MI)-induced CHF. METHODS: The left anterior descending coronary artery (LAD) ligation surgery was performed to establish an MI-induced CHF model in male C57BL/6 mice. From 1 day after surgery, mice were given NXK (0.41, 0.82 or 1.65 g/kg/d), Perindopril (PDPL, 0.607 mg/kg/d), or an equivalent amount of sterile water by gavage for 28 continuous days. Then, mice were examined for cardiac function, myocardial fibrosis, cardiomyocyte apoptosis, mitochondrial structure and mitophagy levels of cardiomyocytes, etc. In addition, a hypoxic injury model was created using HL-1 cardiomyocytes from wild-type (WT) mice. HL-1 cells were pretreated with or without NXK-containing serum. Mitochondrial function and mitophagy levels were examined in HL-1 cells. RESULTS: In MI-induced CHF mice, cardiac dysfunction, severe cardiac remodeling, elevated levels of oxidative stress, reduced ATP levels, and inhibition of PINK1/Parkin-mediated mitophagy were observed. High-dose NXK treatment (1.65 g/kg/d) significantly improved myocardial energy metabolism, inhibited cardiac remodeling, improved cardiac function, and restored cardiac PINK1/Parkin-mediated mitophagy levels to some extent in MI mice. In vitro, elevated levels of mitochondrial reactive oxygen species (ROS) with impaired mitochondrial membrane potential (ΔΨm) were observed in hypoxic HL-1 cells. While NXK treatment significantly protected cardiomyocytes from hypoxia-induced mitochondrial dysfunction, which is consistent with the in vivo results. Further studies showed that NXK could increase PINK1/Parkin-mediated mitophagy levels in cardiomyocytes, which could be blocked by the mitophagy inhibitor Mdivi-1. CONCLUSION: In conclusion, NXK could prevent cardiac mitochondrial dysfunction and improve cardiac function against MI-induced CHF by promoting Pink1/Parkin-mediated mitophagy, which represents a very prospective strategy for the treatment of CHF.

RT-PCR demonstrates superior sensitivity and specificity in detecting the five neuroblastoma genes compared to the flow cytometry method for measurable residual disease.

Background: Exploring sensitive prognostic methods for patients with relapsed or refractory neuroblastoma (NB) is critical. The five NB genes (NB5) share a common trait: they are highly expressed in NB. Previous studies have identified their expression levels as markers for guiding micrometastasis. This study aimed to explore whether an improved NB5 detection method is superior to flow cytometry for predicting NB metastasis, measurable residual disease (MRD), and prognosis, and whether this result could serve as an independent factor to influence progression-free survival (PFS). Methods: We utilized reverse transcriptase polymerase chain reaction (RT-PCR) to assess the expression of NB5 (CHGA, DCX, DDC, PHOX2B, and TH) in bone marrow (BM), peripheral blood (PB), or cerebrospinal fluid (CSF) samples collected from 71 patients. The correlation between gene expression changes and clinical characteristics, as well as survival rates, based on 113 detections were analyzed. The NB5 detection results' sensitivity and specificity in all 71 patients collected from six research centers with a median follow-up of 14 months were assessed. Results: PB specimens showed 100% concordance with the BM specimens in terms of positive results. Furthermore, the BM specimens exhibited an additional 45.455% (5/11) positive results compared to the 34.091% (30/88) of PB specimens. The BM specimens were positive for NB5 assay, which was significantly higher than the positive results of flow cytometric MRD (15/88, 17.045%). NB5 was mainly expressed in newly diagnosed patients (P=0.043) and positive patients with flow cytometric MRD (P<0.001) or BM morphology (P<0.001). Positive rates of droplet digital PCR (ddPCR) were consistent with those of quantitative RT-PCR (qRT-PCR) in BM (13/18, 72.222%). However, in PB, the positive rate of ddPCR (2/5, 40.000%) was higher than that of qRT-PCR. A total of 38 specimens (BM, PB, CSF) were detected as positive under qRT-PCR. Among the positive results, the analysis revealed a significant difference between the CHGA and TH in pairwise comparisons (P=0.005). PFS analysis showed that among MRD-negative patients, the survival time of the NB5-positive group was significantly lower than that of NB5-negative group (27.408±10.791 vs. 35.961±3.084 months; P=0.034), and in the Cox regression model, risk stratification based on NB5 expression level was an independent prognostic factor for relapsed or refractory disease [95% confidence interval (CI):1.020 to 9.099, hazard ratio (HR) =3.046, P=0.046]. Combining the follow-up results, we found that the sensitivity and specificity of NB5 detection were both 100%. Conclusions: In our study, the improved NB5 detection method showed significantly higher sensitivity in assessing tumor relapse or residual disease compared to flow cytometric MRD. Moreover, it provided a more accurate assessment of treatment efficacy and prognosis. These findings support NB5 detection as an effective method for further stratification and monitoring of patients with relapsed or refractory NB.

Factors associated with prolonged postoperative length of hospital stay after laparoscopic colorectal cancer resection: a secondary analysis of a randomized controlled trial.

BACKGROUND: The postoperative length of hospital stay (PLOS) is an important indicator of surgical quality. We identified perioperative factors that affect prolonged PLOS (PPLOS) after laparoscopic colorectal cancer resection, which is the preferred surgical approach for colorectal cancer, the third most common cancer. METHODS: This study was a secondary analysis of a randomized trial (clinicaltrials.gov ID: NCT03160144) that included 280 patients who underwent laparoscopic colorectal cancer resection. The primary outcome was a PPLOS, defined as a PLOS that was longer than the median PLOS. Baseline, anesthetic, surgical, and postoperative management factors were included in the univariate and multivariate analyses to identify factors influencing PPLOS. RESULTS: The median PLOS was 10 days, and 117 patients had a PPLOS. We identified six influencing factors for PPLOS: preoperative pulse oxygen saturation < 96% (odds ratio [OR], 3.09 [95% confidence interval (CI) 1.38-6.92]; P = 0.006), distant tumor metastasis (OR, 0.34 [95% CI 0.13-0.91]; P = 0.031), the Miles procedure or left hemicolectomy (OR, 4.51 [95% CI 1.67-12.18]; P = 0.003), perioperative surgical events (OR, 2.44 [95% CI 1.25-4.76]; P = 0.009), postoperative albumin infusion (OR, 2.19 [95% CI 1.14-4.19]; P = 0.018), and postoperative early ambulation (OR, 0.35 [95% CI 0.18-0.68]; P = 0.002). Further stratified analysis showed that postoperative albumin infusion might be a risk factor for PPLOS, even in patients with a preoperative albumin level < 40 g/L (OR, 2.29 [95% CI 0.98-5.34]; P = 0.056) or duration of surgery ≥ 3 h (OR, 2.52 [95% CI 1.08-5.87]; P = 0.032). CONCLUSIONS: A low preoperative pulse oximetry reading, complex surgical procedures, perioperative surgical events, and postoperative albumin infusion may be risk factors for PPLOS after laparoscopic colorectal cancer resection, whereas distant tumor metastasis and postoperative early ambulation might be protective factors. The association between postoperative albumin infusion, a modifiable factor, and PLOS or clinical outcomes warrants further investigation.

Immunotherapy and Prognosis of Non-small Cell Lung Carcinoma by Monomethoxy polyethylene glycol-hyaluronic acid-platinum Combined with Immune CT4+ and CT8+ Detection.

To investigate the changes in CT4+ and CT8+ lymphocyte subpopulations of patients with non-small cell lung carcinoma (NSCLC) by monomethoxy polyethylene glycol-hyaluronic acid-platinum (MPEG-HA-Pt) and the correlation between efficacy evaluation and the changes in T lymphocyte subpopulation, 76 NSCLC patients treated at oncology department of Chengdu First People's Hospital were selected and randomly divided into the treatment group and the control group (38 cases in each). mPEG-HA-Pt was used for the treatment of the included patients in the research. The patients in the control group were performed with traditional chemotherapy for 2 treatment courses. The changes in the T-lymphocyte subpopulation before and after the treatment were detected and the therapeutic effects on the patients in the two groups were compared. The particle size of mPEG-HA-Pt ranged between 78nm and 100nm with an average of 84.6±7.5nm. After that, a transmission electron microscope (TEM) was used to observe the spheres with uniform size. The drug loading capacity and entrapped efficiency of mPEG-HA-Pt were 18.7% and 87.4%, respectively. After the treatment for NSCLC patients by nanomicelle, cellular immune functions were all improved. In particular, cellular immune functions of the patients with good efficacy evaluation were improved more apparently.

Nanoflare Couple: Multiplexed mRNA Imaging and Logic-Controlled Combinational Therapy.

Theranostics, which combines both diagnostic and therapeutic capabilities in one dose, has always been an intractable challenge in personalized cancer treatment. Herein, a versatile nanotheranostic platform "nanoflare couple (NC)" has been developed for in situ multiplex cancer-related mRNA imaging and subsequent logic-controlled aggregation of gold nanoparticles, leading to gene therapy and photothermal therapy upon irradiation with infrared light. As a proof of concept, TK1 and survivin mRNAs that are highly expressed in most tumor tissues are selected as endogenous cancer indicators and therapy triggers to design the NC. Mice bearing breast cancer cells MCF-7 are prepared as a model to test its efficacy. The in vitro and in vivo assays validate that the NC show the capability for multiplexed mRNA imaging and high efficiency for logic-controlled combinational therapy of breast cancer.

Nuanxinkang protects against ischemia/reperfusion-induced heart failure through regulating IKKß/IκBα/NF-κB-mediated macrophage polarization.

BACKGROUND: Heart failure (HF) is a leading cause of death worldwide. Nuanxinkang (NXK) is an effective Chinese herbal formula used in treating HF, but its underlying potential mechanisms have not been fully elucidated. PURPOSE: To explore the protective activities of NXK in ischemia/reperfusion (IR)-induced HF through modulating the ratio of proinflammatory (M1) and anti-inflammatory (M2) macrophage populations and leading to the alleviation of inflammation. MATERIALS AND METHODS: In vivo, mice were subjected to myocardial IR to generate HF mouse models. Mice in the NXK group were treated with NXK for 28 days. Cardiac function was detected by echocardiography. Major lesions on mouse hearts were determined by hematoxylin-eosin (HE) staining, Masson staining, and TUNEL staining. Inflammatory cytokines were determined by enzyme-linked immunosorbent assay (ELISA) and qPCR examination. Flow cytometric analyses and qPCR examination were utilized for monitoring the temporal dynamics of macrophage infiltration following IR. In vitro, two polarized models were established by stimulating RAW264.7 cells with 200 ng/ml lipopolysaccharide (LPS) or 20 ng/ml interleukin-4 (IL-4). The RAW264.7 cells with nuclear factor-κB (NF-κB) overexpression was generated by transient transfection of NF-κB plasmids, and NXK intervention was conducted on this cell model to further clarify the involvement of NF-κB signaling in the NXK-mediated HF process. RESULTS: In the present study, NXK was found to significantly contribute the cardiac function and ameliorate cardiac fibrosis and apoptosis after myocardial IR injury in vivo, which may be partially due to a decrease in inflammation. We therefore hypothesized that NXK reduced inflammatory damage by modulating subtypes of macrophages. And the results demonstrated that the percentage of proinflammatory macrophages infiltrated in the post-IR period was reduced with NXK treatment, and thereby blunting the wave of proinflammatory response and shifting the peak of the anti-inflammatory macrophage-mediated wound healing process towards an earlier time point. The further investigation showed that macrophage polarization was mediated by NXK through inhibiting the phosphorylation and the nuclear translocation of NF-κB. Besides, the phosphorylated IKKß and IκBα, upstream mediators of the NF-κB pathway, also decreased by NXK. Moreover, the overexpression of NF-κB partially reversed the NXK-induced favorable activities; and successfully compensated the suppressive effect on inflammation and the phosphorylation of NF-κB. CONCLUSION: In conclude, our results demonstrated that NXK induced the cardioprotective effects against IR injury through a regulatory axis of IKKß/IκBα/NF-κB-mediated macrophage polarization. The information gained from this study provide a possible natural strategy for anti-inflammatory treatment of HF.

Long-term safety and absorption assessment of a novel bioresorbable nitrided iron scaffold in porcine coronary artery.

This study aimed to investigate the long-term biocompatibility, safety, and degradation of the ultrathin nitrided iron bioresorbable scaffold (BRS) in vivo, encompassing the whole process of bioresorption in porcine coronary arteries. Fifty-two nitrided iron scaffolds (strut thickness of 70 µm) and 28 Vision Co-Cr stents were randomly implanted into coronary arteries of healthy mini-swine. The efficacy and safety of the nitrided iron scaffold were comparable with those of the Vision stentwithin 52 weeks after implantation. In addition, the long-term biocompatibility, safety, and bioresorption of the nitrided iron scaffold were evaluated by coronary angiography, optical coherence tomography, micro-computed tomography, scanning electron microscopy, energy dispersive spectrometry and histopathological evaluations at 4, 12, 26, 52 weeks and even at 7 years after implantation. In particular, a large number of struts were almost completely absorbed in situ at 7 years follow-up, which were first illustrated in this study. The lymphatic drainage pathway might serve as the potential clearance way of iron and its corrosion products.

Tucatinib has Selective Activity in HER2-Positive Cancers and Significant Combined Activity with Approved and Novel Breast Cancer-Targeted Therapies.

Pharmacologically targeting the HER2 oncoprotein with therapeutics such as the mAb, trastuzumab, provides clinical benefit for patients with HER2-positive (HER2+) cancers. However, a significant number of patients eventually progress on these therapies. Efforts to overcome therapeutic resistance through combination therapy with small-molecule inhibitors of HER2 have been limited by toxicities associated with off-target activity and/or limited efficacy. In this preclinical study, we explore single-agent and combined activity of tucatinib, a novel HER2-selective small-molecule inhibitor. Tucatinib demonstrated potent, selective activity in a panel of 456 human cancer cell lines, with activity restricted to cell lines (breast and non-breast) with HER2-amplification, including models of acquired resistance to trastuzumab. Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single-agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard-of-care trastuzumab/pertuzumab/docetaxel combination, with the exception that the chemotherapy-sparing tucatinib/trastuzumab combination did not require a dosing holiday to achieve the same efficacy. In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER; HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer. These data support expanded clinical investigations of tucatinib as a combination partner for other novel and approved targeted therapies for HER2-driven malignancies.

Apoptosis-Promoting Effects on A375 Human Melanoma Cells Induced by Exposure to 35.2-GHz Millimeter Wave.

Malignant tumors pose a major problem in the medical field. Millimeter wave (MMW) exposure have potential apoptosis-promoting effects on several types of tumors. Considering that the penetration depth of millimeter wave is usually several millimeters, we study the apoptosis-promoting effects of millimeter wave exposure on A375 human melanoma tumor cells in vitro, and this topic has not been explored in the previous literature. In this study, we use the A375 human melanoma cell line as an experimental model exposed to 35.2 GHz millimeter wave in vitro to determine any positive effect and further explore the underlying mechanisms. In this study, 2 groups namely, exposed and sham groups, were set. The exposed groups included 4 exposure time periods of 15, 30, 60, and 90 minutes. The cells in the sham group did not receive millimeter wave exposure. After millimeter wave exposure, the A375 cells in the exposed and sham groups were collected for further experimental procedures. The cell viability after exposure was determined using a cell counting kit, and the apoptosis of A375 cells was assessed by Annexin V/propidium iodide. Changes in the expression of apoptosis-related proteins, including cleaved-caspase-3, and -8, were examined by Western blot. We observed that the millimeter wave exposure could inhibit the viability and induce apoptosis in A375 cells, and the expression of cleaved caspase-3 and -8 were upregulated (P < .05). The results indicated that the millimeter wave at 35.2 GHz exerted apoptosis-promoting effects on the A375 cells via a pathway by activating of caspase-8 and -3.

Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer.

BACKGROUND: Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. METHODS: In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. RESULTS: We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models. CONCLUSIONS: These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

Neuroimaging findings of cerebral syphilitic gumma.

Cerebral syphilitic gumma is a rarely reported disease of the central nervous system. Magnetic resonance imaging (MRI) is an important diagnostic method for syphilitic gumma. The present study aimed to describe and characterize neuroimaging results from 6 patients with pathologically diagnosed cerebral syphilitic gumma. The 6 patients (age, 32-61 years) underwent brain CT and MRI, with 1 patient also undergoing whole-body 2-deoxy-2-(fluorine-18)fluoro-D-glucose-positron emission tomography/CT (18F-FDG PET/CT). Non-enhanced CT, conventional T1 weighted imaging (T1WI) and T2WI, diffusion weighted imaging (DWI) and gadolinium-enhanced T1WI images were acquired for all patients. The CT and MRI scans were retrospectively reviewed by two experienced radiologists for consensus on the location, number, size, T1WI, T2WI and DWI signal intensity characteristics, extent of vasogenic oedema, and enhancement patterns. In total, the 6 patients exhibited 10 lesions, nine of which were located in the cerebral hemisphere, primarily in the grey matter. The remaining lesion was located in the fourth ventricle, leading to mild-to-moderate hydrocephalus. The diameters of the identified 10 lesions ranged from 0.9-6.5 cm, with a mean diameter of 3.9 cm. The main feature observed in CT was low density and in MRI the features were T1WI and DWI hypointensity and T2WI hyperintensity. A single case exhibited syphilis gumma with massive haemorrhage. Ring-like or strip-like signs (n=5), accompanied by the dural tail sign (n=2) and homogeneous enhancement (n=1), were noted on T1WI with gadolinium. The 18F-FDG PET/CT performed in one patient of a cerebral syphilis gumma revealed low uptake and metabolism. The present study indicated that gadolinium-enhanced MRI combined with 18F-FDG PET/CT and laboratory examinations are helpful in distinguishing cerebral syphilitic gumma from brain tumors and infectious diseases, therefore avoiding unnecessary surgery.

A simplified herbal formula for the treatment of heart failure: Efficacy, bioactive ingredients, and mechanisms.

Heart failure (HF) is a complex pathology for which single-agent therapy cannot provide comprehensive efficacy. Therefore, effective combination therapies for HF are increasingly emphasized. Multiple-component drugs derived from Chinese herbal formulae provide efficacy and safety when administered to patients with HF. Nuanxinkang (NXK) is a simplified Chinese herbal formula which has been widely applied in HF for decades. It exhibits comprehensive cardiac protective effects in HF patients as an adjuvant therapy, including improving heart function and quality-of-life, reducing inflammation, and regulating neurohormones. Nevertheless, the bioactive ingredients and mechanisms of action of NXK are unknown, which hinders its further application. Here, we examined the therapeutic efficacy of NXK in a mouse model of HF. Using transcriptome analysis and drug similarity analysis we found that NXK inhibits apoptosis and inflammation, while improving cardiac contraction and reversing myocardial fibrosis. In addition, we detected 21 bioactive species in NXK using UHPLC-MS analysis. Based on these data, we performed network pharmacology analysis to investigate ingredient-target-pathway interactions. We further confirmed 13 genes as potential targets, and assessed the effects of NXK on the AKT to validate the anti-apoptotic role of NXK both in vivo and in vitro. Thus, our work has identified a simplified herbal formula with efficacy against HF by exploring its constituents and mechanism of action, providing evidence for an innovative treatment strategy and novel therapeutic targets for HF.

Preclinical Evaluation of a Novel Sirolimus-Eluting Iron Bioresorbable Coronary Scaffold in Porcine Coronary Artery at 6 Months.

OBJECTIVES: The aim of this study was to investigate the operability, 6-month efficacy, and safety of the novel sirolimus-eluting iron bioresorbable coronary scaffold (IBS) system compared with a cobalt-chromium everolimus-eluting stent (EES) (XIENCE Prime stent) in porcine coronary arteries. BACKGROUND: Bioresorbable scaffolds have been considered the fourth revolution in percutaneous coronary intervention. However, the first-generation bioresorbable scaffold showed suboptimal results. METHODS: Forty-eight IBS and 48 EES were randomly implanted into nonatherosclerotic swine. The operability, efficacy, and safety of the IBS and EES were evaluated using coronary angiography, optical coherence tomography, micro-computed tomography, scanning electron microscopy, and histopathologic evaluation at 7, 14, 28, 90, and 180 days after implantation. RESULTS: The operability of the ultrathin IBS (∼70 µm) was comparable with that of the EES, except for its visibility. There was no statistically significant difference in area stenosis between the IBS and EES from 28 to 180 days. The IBS maintained its integrity up to 90 days without corrosion, while corrosion was observed in a few struts in 2 of 10 IBS at 180 days. The percentage of endothelialization of IBS was higher than that of XIENCE Prime stents within 14 days after implantation. The fibrin score was higher in the IBS group at 28 days but comparable with the EES group at 90 and 180 days. No scaffold or stent thrombosis was seen in either group. No abnormal histopathologic changes in scaffolded or stented vessel segments and 5 main remote organs were observed in either group. CONCLUSIONS: Preclinical results suggest that the novel IBS has comparable operability, mid-term efficacy, and safety with the EES, and its corrosion profile in porcine coronary arteries is reasonable, which could support initial clinical study of the IBS.

[Millimeter wave exposure induces apoptosis in human melanoma A375 cells in vitro].

OBJECTIVE: To investigate the effects of millimeter wave (MMW) exposure on apoptosis of human melanoma A375 cells and explore the mechanisms. METHODS: Through electromagnetic field calculation we simulated MMW exposure in cells and calculated the specific absorption rate (SAR). The optimal irradiation parameters were determined according to the uniformity and intensity of the SAR. A375 cells were then exposed to MMV for 15, 30, 60, or 90 min, with or without pretreatment with the caspase-3 inhibitor AC-DEVD-fmk (10 µmol/L) for 1 h at 90 min before the exposure. CCK-8 assay was used to assess the changes in the viability and Annexin-V/ PI staining was used to detect the apoptosis of the cells following the exposures; Western blotting was used to detect the expression of caspase-3 in the cells. RESULTS: The results of electromagnetic field calculation showed that for optimal MMV exposure, the incident field needed to be perpendicular to the bottom of the plastic Petri dish with the antenna placed below the dish. CCk-8 assay showed that MMW exposure significantly inhibited the cell viability in a time-dependent manner (P < 0.05); exposures for 15, 30, 60, and 90 min all resulted in significantly increased apoptosis of the cells (P < 0.05). The cells with MMW exposure showed significantly increased expression of caspase-3. The inhibitory effect of MMW on the cell viability was antagonized significantly by pretreatment of the cells with AC-DEVD-fmk (P < 0.05), which increased the cell viability rate from (36.7±0.09)% to (59.8±0.06)% (P < 0.05). CONCLUSIONS: 35.2 GHz millimeter wave irradiation induces apoptosis in A375 cells by activating the caspase-3 protein.

Characterization of long non-coding RNAs to reveal potential prognostic biomarkers in hepatocellular carcinoma.

Dysregulation of long non-coding RNAs (lncRNAs) plays critical roles in a variety of biological processes. Recent studies have documented that lncRNAs can function as potential biomarkers in cancer prognosis, however, little is known in hepatocellular carcinoma (HCC). To identify lncRNA signatures that have prognostic values in HCC, we analyzed lncRNA expression profiles of 364 HCC patients from The Cancer Genome Atlas (TCGA) dataset. A set of four lncRNAs was identified to be significantly associated with the overall survival. Based on the four-lncRNA signature, HCC patients can be classified into high- and low-risk subgroups with significantly different survival. This result can be further validated in the testing set and another independent HCC data. Further analyses showed that the prognostic value of four-lncRNA signature was independent of other clinicopathological factors. The potential functions of candidate lncRNAs were further examined using HCC cell lines, suggesting these lncRNAs might contribute to tumor development of HCC. This work indicated that lncRNA signature could be a useful marker to determine the diagnosis and predict the prognosis of HCC.

MKAD-21 Suppresses the Oncogenic Activity of the miR-21/PPP2R2A/ERK Molecular Network in Bladder Cancer.

Bladder cancer represents a disease associated with significant morbidity and mortality. MiR-21 has been found to have oncogenic activity in multiple cancers, including bladder cancer, whereas inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in bladder cancer and evaluate the effects of i.v. and i.p. administration of a novel miR-21 chemical inhibitor in vivo LNA miR-21 reduced the oncogenic potential of bladder cancer cells, whereas the MKAD-21 chemically modified antisense oligo against miR-21 dose-dependently blocked xenograft growth. I.v. administration of LNA miR-21 was more effective in suppressing tumor growth than was i.p. administration. Integration of computational and transcriptomic analyses in a panel of 28 bladder cancer lines revealed a 15-gene signature that correlates with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit Balpha (PPP2R2A) was one of these 15 genes and was experimentally validated as a novel miR-21 direct target gene. Gene network and molecular analyses showed that PPP2R2A is a potent negative regulator of the ERK pathway activation and bladder cancer cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21-induced oncogenic effects in bladder cancer. Integrative analysis of human bladder cancer tumors and a large panel of human bladder cancer cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. Importantly, we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and bladder cancer cell growth. Furthermore, i.v. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A-ERK network in mice. Mol Cancer Ther; 17(7); 1430-40. ©2018 AACR.